G protein coupled receptor (GPCR) signaling pathways mediate actions of hormones and neurotransmitters. They are essential for normal function of the nervous system and are frequently disrupted, and/or exploited for therapeutic purposes, in many neuropsychiatric and neurological conditions. While we learned considerable information about molecular players involved in shaping GPCR signal transmission there are many critical gaps in our understanding of mechanisms pertaining to signaling regulation. Among biggest uncharted territories in GPCR field is an issue of orphan receptors, GPCR-like molecules with unknown signaling mechanisms. It is generally recognized that orphan receptors have tremendous potential for uncovering novel biology of the nervous system and harnessing it for potential therapeutic benefits. Our long- term goal is to understand principles for organizatio and functional regulation of GPCR pathways in the effort to develop better treatments for brain disorders. The focus of our attention is on the Regulators of G protein Signaling (RGS) proteins that terminate G protein signaling and are increasingly viewed as regulatory hubs for signal transmission in the GPCR pathways. We have found that a member of RGS family, RGS7 plays essential role in mood regulation. Investigating the mechanisms of its action revealed that it controls the activity of the inhibitory G protein Inwardly rectifying K+ (GIRK) channels and that i the brain it forms tight complexes with previously uncharacterized orphan receptor, GPR158. Our preliminary data suggest that GPR158 is involved in determining activity, localization and expression of RGS7 and thus may represent an essential new GPCR signaling component. Intriguingly, knockout of either GPR158 or RGS7 in mice results in a prominent reduction in anxiety/depression-related behaviors. Based on accumulated preliminary data we hypothesize that GPR158 is the critical regulator of G protein signaling that act by modulating the function of RGS7 proteins in the nervous system. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to: (1) determine mechanisms, by which GPR158 regulates catalytic activity of RGS7, (2) analyze the role of GPR158 in controlling expression and localization of RGS7 in the brain and (3) determine contribution of GPR158 to regulation of GIRK channels and neuronal excitability. The strategy proposed to address these Aims will entail a synergistic combination of biochemical, electrophysiological and cell-biological approaches, exploiting the existence of a powerful array of reagents and animal models. We hope that accomplishment of these goals will provide critical new insights into the mood regulation in mammals and suggest novel targets for the development of therapeutic interventions.